Antiphlogistic pharmaceutical compositions and method of use

ABSTRACT

Pharmaceutical compositions containing a non-steroidal anti-inflammatory compound and 5,11-dihydro-11-[(4-methyl-1-piperazinyl)-acetyl]-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one or a non-toxic acid addition salt thereof, and a method of using the same as antiphlogistics; the pyridobenzodiazepinone ingredient effectively suppresses the gastro-intestinal side-effects of the anti-inflammatory ingredient.

This is a continuation-in-part of copending application Ser. No. 878,904 filed Feb. 17, 1978, now U.S. Pat. No. 4,154,833.

This invention relates to novel non-ulcerogenic antiphlogistic pharmaceutical compositions containing, in combination, a non-steroidal anti-inflammatory ingredient and a pyridobenzodiazepinone.

BACKGROUND OF THE INVENTION

A number of different authors, including Katz et al. in Clin. Pharmacol. Ther. 6, 25 (1965); Bhargava et al. in Europ. J. of Pharmacol. 22, 191-195 (1973); Leonard et al. in Clin. Pharmacol. and Ther. 14 (1), 62-66 (1973); Lee et al. in Arch. Int. Pharmacodyn. 19, 370-377 (1971); and Somogyi et al. in J. Pharm. Pharmacol. 21, 122 (1969) have reported or confirmed that non-steroidal antiphlogistics produce an undesirable side-effect in that they cause gastrointestinal bleeding and lead to ulcerations of varying degrees, which often requires the discontinuance of a very necessary therapeutic treatment.

Non-steroidal antiphlogistics which are clinically used for symptomatic antiphlogistic therapy are primarily indomethacin, phenylbutazone and azapropazone. Rheumatologists are familiar with the problem of the gastro-intestinal incompatability of these symptomatic antiphlogistics, which often leads to discontinuance of or a change in the prescribed therapy. Depending upon experience, the spectrum of patients and the particular compound which is primarily used, the above described incompatabilities are encountered in 25-37% of all cases.

For want of acceptable alternatives, antacids, succus liquiritiae-preparations or carbenoxolone are, now as before, still used as a means of avoiding these side-effects.

While it is possible to achieve initial success with antacids and succus liquiritiae-preparations, their use over extended periods of time, even after a few weeks, does not provide a reliable protective effect for the mucous membrane of the gastro-intestinal tract.

The above-described undesirable side-effects can be favorably influenced with carbenoxolone, but definitive results are obtained only after long-term use. However, in 20% of the cases the long-term use of carbenoxolone produces undesirable side-effects of different types (43% edema, 36% hypokalemia, 6% hypertension); in patients above 60 years of age, these side-effects even occur in 75% of all cases.

The importance of a meaningful prophylaxis of gastrointestinal side-effects after administration of non-steroidal antiphlogistics becomes particularly significant in the case of those diseases which require life-long antiphlogistic therapy, such as Bechterew's disease and primary chronic polyarthritis. An investigation of this aspect at one of the largest rheumatism centers in the Federal Republic of Germany has shown that over a period of one year about 450 changes in therapeutic treatment per 100 patients afflicted with Bechterew's disease or primary chronic polyarthritis had to be made because of severe gastrointestinal side-effects resulting from long-term treatment with non-steroidal antiphlogistics.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide antiphlogistic pharmaceutical compositions containing a non-steroidal anti-inflammatory compound as well as a compound which effectively suppresses the undesirable gastro-intestinal side-effects of the non-steroidal anti-inflammatory agent without interfering with the desired antiphologistic activity thereof.

Other objects and advantages of the invention will become apparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION

We have discovered that the above object is achieved by antiphlogistic pharmaceutical compositions containing, in combination, a non-steroidal anti-inflammatory compound and 5,11-dihydro-11-[(4-methyl-1-piperazinyl)-acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (generic name: pirenzepine) or a non-toxic, pharmaceutically acceptable acid additional salt thereof, especially its dihydrochloride.

The fact that it has until now not been possible to separate the ulcerogenic side-effects of non-steroidal antiphlogistics from their desired anti-inflammatory activity (see Goodman and Gilman, The Pharmacological Basis of Therapeutics, 5th Ed., pages 325-358, The Macmillan Co., New York, 1975) strongly suggests that both effects must be caused by the same mechanism. Thus, our discovery, that by simultaneously administering a non-steroidal antiphlogistic and pirenzepine or a non-toxic acid addition salt thereof the gastro-intestinal side-effects are to a large extent or completely suppressed while the antiphlogistic effect is neither weakened nor antagonized, is entirely unobvious and unexpected. In fact, when administered together with pirenzepine or a non-toxic acid addition salt thereof, non-steroidal antiphlogistics can be safely administered at such high dosage levels which would otherwise not be tolerated.

For instance, we have been able to show that by administering pirenzepine dihydrochloride together with indomethacin, the so-called ulcer rate of 37% was reduced to virtually 0%. This data is based on observations made on several hundred cases over a period of two years.

Daily doses of 10 to 30 mgm have been shown in clinical tests to be sufficient to suppress the gastro-intestinal side-effects caused by all therapeutically employed non-steroidal antiphlogistics. Based on the favorable pharmacokinetics of pirenzepine and its dihydrochloride, single therapeutic doses administered at 12-hour intervals are sufficient to assure round-the-clock mucous membrane protection.

It should also be mentioned that, under the protection of pirenzepine, it is also possible to increase the dosage of non-steroidal antiphlogistics without having to expect incompatabilities.

We have not observed any incompatabilities between pirenzepine and non-steroidal antiphlogistics.

Furthermore, we investigated by pharmacological tests to what extent pirenzepine dihydrochloride (A) produces a protective effect on the stomach of rats against the ulcerogenic effect of the following non-steroidal antiphlogistics:

(B) Indomethacin=1-(4-chloro-benzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid,

(C) 4-[4-(2'-fluoro-biphenylyl)]-4-hydroxy-crotonic acid morpholine salt,

(D) 4-(4-biphenylyl)-butanol,

(E) Diclofenac=sodium [o-(2,6-dichloro-anilino)-phenyl]-acetate,

(F) Naproxen=d-2-(6-methoxy-2-naphthyl)-propionic acid,

(G) Phenylbutazone=4-butyl-1,2-diphenyl-3,5-pyrazolidinedione, and

(H) Ibuprofen=2-(4-isobutylphenyl)-propionic acid.

In addition, we investigated whether the simultaneous administration of pirenzepine dihydrochloride weakened the acute anti-inflammatory effect of the above non-steroidal anti-phlogistics.

METHOD

(1) Test for ulcerogenic effect on the stomach of the rat

The test was carried out on male and female (1:1) Chbb:THOM-rats with a body weight between 130 to 150 gm at the beginning of the study.

The test substances (non-steroidal anti-phlogistics or mixtures of these antiphlogistics with pirenzepine dihydrochloride) were administered as triturations in 1% tylose (1 ml/100 gm animal) by way of an esophageal tube once a day on three successive days.

Four hours after the last administration (i.e. on the 3rd day) the animals were killed by an over-dose of ether. The stomachs wer dissected, cut along the great curvature and washed under flowing water for subsequent macroscopic evaluation.

From the percentage of animals which, after different dosages, showed at least one stomach ulcer or one hemorrhagic erosion, using the method of LITCHFIELD and WILCOXON [J. Pharmacol. exp. Ther. 96, 99 (1949)], the ED₅₀ of the different non-steroidal antiphlogistics with or without the addition of pirenzepine dihydrochloride was calculated as the dose which was ulcerogenic in 50% of the animals.

(2) Test for antiphlogistic effect against the kaolin-induced edema of the rat's hind paw (tested substances: A, B, C and D

The test was carried out on male Chbb:THOM-rats with a body weight between 125 and 150 gm. According to HILLEBRECHT [Arzneimittel-Forsch. 4, 607 (1954)], a subplantary injection of 0.05 ml of a 10% suspension of kaolin in an aqueous 0.85% sodium chloride solution in the hind paw was used for the provocation of the kaolin edema. The other hind paw was subplantarily injected with the same volume of an aqueous 0.85% sodium chloride solution.

The measurement of the thickness of the paws was carried out using the technique of DOEPFNER and CERLETTI [Int. Arch. Allergy appl. Immunol. 12, 89 (1958)] by way of the determination of the maximum sagittal diameter, using a measuring device with constant pressure, before and 5 hours after the provocation of the edema.

The test substances (the non-steroidal antiphlogistics or the mixture of non-steroidal antiphlogistics with pirenzepine dihydrochloride) were administered 30 minutes before provocation of the edema as a trituration in 1% tylose (1 ml/100 mgm animal) by way of an esophageal tube.

The diameter of the paw measured before the beginning of the test as well as the increase in diameter of the other paw caused by injection were subtracted from the diameter of the kaolin-treated paw, and this difference, being the real swelling value, was used for the further calculations.

(3) Test for antiphlogistic effect against the carrageenin-induced edema of the hind paw of the rat (test substances: A, E, F, G and H)

The test was carried out in analogy to the above test for the kaolin-induced edema. However, the edema was induced according to the method of WINTER et al. [J. Pharmacol. 141, 369 (1963)] by subplantary injection of 0.05 ml of a 1% solution of carrageenin in an aqueous 0.85% solution of sodium chloride. The test substances (non-steroidal antiphlogistics or their mixtures with substance A) were administered 60 minutes before provocation of the edema as a trituration in 1% methyl cellulose (1 ml/100 gm animal), by way of an esophageal tube. Three hours after the provocation of the edema the measurement which provided the basis for the evaluation of an anti-exudative effect was carried out.

From the swelling values obtained by administration of different dosages of non-steroidal antiphlogistics with or without the addition of pirenzepine dihydrochloride, using a linear regression analysis according to LINDNER [Statistische Methoden, 4th Ed., pages 148-162, Birkhauser, Basel, Switzerland (1964)], the ED₃₅ values of the antiphlogistics were calculated with the confidence limits according to FIELLER [Quart. J. Pharm. Pharmacol. 17, 117 (1944)], the ED₃₅ being the dosage which reduces the swelling of the paws by 35% in comparison to the control animals.

The following tables show the values obtained:

                  TABLE I                                                          ______________________________________                                         Effectiveness of A against the ulcerogenic effect of B, C                      and D in the gastro-intestinal tract of the rat after                          combined oral administration on 3 subsequent days.                             Antiphlo-        A        Ratio of                                             gistic  Dosage   Dosage   animals with                                                                             ED.sub.50 -ulcer*                          compound                                                                               mgm/kg   mgm/kg   ulcers    mgm/kg                                     ______________________________________                                         B       2.0      --       4/18      2.55                                       B       2.8      --       11/18     (2.16-3.01)                                B       4.0      --       16/18                                                B       2.8       50      4/16      3.30                                       B       4.0       50      12/16     (2.66-4.09)                                B       5.66      50      13/15                                                B       2.8      100      4/16                                                 B       4.0      100      5/15      4.90                                       B       5.66     100      8/15      (3.88-6.17)                                B       8.0      100      15/15                                                C       52       --       5/12      54.5                                       C       62       --       8/12      (47.0-63.2)                                C       74       --       10/12                                                C       62        50      4/15                                                 C       74        50      8/17      83.0                                       C       88        50      9/17      (70.2-98.1)                                C       106       50      11/17                                                C       74       100      0/15                                                 C       88       100      4/15      151                                        C       106      100      3/15      (117-195)                                  C       127      100      7/15                                                 C       153      100      8/15                                                 D       28.1     --       4/17                                                 D       37.5     --       5/17      44.5                                       D       50.0     --       9/17      (38.0-52.1)                                D       67.5     --       15/17                                                D       50.0      50      1/16                                                 D       67.5      50      6/16      75.0                                       D       91.1      50      11/14     (63.6-88.5)                                D       123.0     50      13/14                                                D       50.0     100      2/16                                                 D       67.5     100      5/15      88.5                                       D       91.1     100      7/15      (72.0-108.9)                               D       123.0    100      10/13                                                E       2        --       5/20      2.95                                       E       4        --       14/20     (2.27-3.84)                                E       8        --       19/20                                                E       2        200      3/20      4.05                                       E       4        200      9/20                                                 E       8        200      17/19     (2.79-5.87)                                E       16       200      20/20                                                E       2        400      1/20      5.63                                       E       4        400      7/20                                                 E       8        400      13/20     (4.02-7.88)                                E       16       400      19/20                                                F       1.25     --       2/19      3.6                                        F       2.5      --       4/19                                                 F       5.0      --       15/19     (2.62-4.95)                                F       10.0     --       16/19                                                F       1.25     200      1/20      7.9                                        F       2.5      200      4/20                                                 F       5.0      200      6/20      (5.5-11.3)                                 F       10.0     200      10/20                                                F       20.0     200      17/20                                                F       1.25     400      1/20      10.45                                      F       2.5      400      0/20                                                 F       5.0      400      5/20      (6.97-15.68)                               F       10.0     400      10/20                                                F       20.0     400      14/20                                                G       50       --       4/20      69.0                                       G       100      --       14/20                                                G       200      --       20/20     (55.6-85.6)                                G       50       200      2/20      78.0                                       G       71       200      8/20                                                 G       100      200      15/20     (66.7-91.3)                                G       200      200      20/20                                                G       50       400      0/20      138.0                                      G       71       400      0/20                                                 G       100      400      6/20      (102.2-186.3)                              G       200      400      14/20                                                G       400      400      18/19                                                H       12.5     --       0/20      31.0                                       H       25       --       8/20                                                 H       50       --       15/20     (23.0-41.9)                                H       100      --       19/20                                                H       200      --       20/20                                                H       25       100      6/20      41.5                                       H       50       100      11/20                                                H       100      100      18/20                                                H       200      100      20/20     (29.6-58.1)                                H       25       400      1/20      52.7                                       H       50       400      11/20                                                H       100      400      16/20     (37.7-74.0)                                H       200      400      19/20                                                ______________________________________                                          *calculated according to LITCHFIELD and WILCOXON: confidence limits with       95% probability in parentheses.                                          

                  TABLE II                                                         ______________________________________                                         Influence of A on the acute-exudative effect of B, C                           and D against the kaolin-induced edema of the hind paw of                      the rat, after simultaneous oral administration.                                                            Thickness                                         Antiphlo-                    of the                                            gistic          A            paw in 10.sup.-2                                                                       ED.sub.35 mgm/kg                          com-   Dosage   Dosage       mm      (confidence                               pound  mgm/kg   mgm/kg   n*  -x   s    limits)                                 ______________________________________                                         Controls                                                                              --       --       20  271.3                                                                               13.7                                         B      1.5      --       20  214.8                                                                               21.6 4.3                                     B      3.0      --       19  189.0                                                                               16.5 (3.7-5.2)                               B      6.0      --       20  164.5                                                                               18.6                                         Controls                                                                              --       100      20  277.5                                                                               21.2                                         B      1.5      100      20  200.3                                                                               19.2 3.0                                     B      3.0      100      20  178.3                                                                               19.4 (2.5-3.6)                               B      6.0      100      19  162.9                                                                               15.3                                         Controls                                                                              --       --       19  268.7                                                                               13.5                                         C      6.25     --       18  203.9                                                                               22.9 15.3                                    C      12.5     --       19  179.5                                                                               17.0 (13.5-17.1)                             C      25       --       20  164.3                                                                               17.9                                         C      50       --       20  138.0                                                                               13.4                                         C      100      --       20   93.8                                                                               17.0                                         Controls                                                                              --       100      15  276.3                                                                               14.9                                         C      6.25     100      15  215.6                                                                               24.3 17.6                                    C      12.25    100      15  187.0                                                                               21.2 (14.4-21.5)                             C      25       100      15  166.0                                                                               29.5                                         C      50       100      15  149.3                                                                               18.4                                         Controls                                                                              --       --       45  269.5                                                                               12.5                                         D      6.25     --       15  214.3                                                                               18.6 11.2                                    D      12       --       15  165.0                                                                               19.0 (9.95-12.4)                             D      25       --       15  124.0                                                                               29.8                                         Controls                                                                              --       100      20  278.0                                                                               14.8                                         D      6.25     100      20  215.5                                                                               21.5 12.1                                    D      12       100      20  180.4                                                                               13.4 (11.1-13.2)                             D      25       100      20  141.0                                                                               17.9                                         ______________________________________                                          *n = No. of animals                                                      

                  TABLE III                                                        ______________________________________                                         Influence of A on the acute anti-exudative effect of E,F,                      G and H, against the carrageenin-induced edema of the rat's                    hind paw after simultaneous administration.                                    Antiphlo-                    Thickness                                         gistic          A            of the paw                                                                             ED.sub.35 mgm/kg                          com-   Dosage   Dosage        in 10.sup.-2 mm                                                                       (confidence                               pound  mgm/kg   mgm/kg   n*  -x   s    limits)                                 ______________________________________                                         Controls                                                                              --       --       20  278.8                                                                               16.4 51.7                                    G      25                19  216.8                                                                               14.8                                         G      50       --       20  175.8                                                                               15.8 (46.6-56.9)                             G      100      --       20  153.8                                                                               17.1                                         G      200      --       20  125.0                                                                               20.2                                         Controls                                                                              --       400      10  272.0                                                                               24.6 45.7                                    G      25       400      10  205.0                                                                               27.0                                         G      50       400      10  173.5                                                                               21.9 (36.6-55.9)                             G      100      400       9  138.9                                                                               25.8                                         Controls                                                                              --       --       10  267.0                                                                               22.9 39.6                                    H      20       --       10  210.0                                                                               28.2                                         H      40       --       10  167.0                                                                               16.2 (33.6-45.9)                             H      80       --       10  141.5                                                                               15.8                                         Controls                                                                              --       400      10  272.0                                                                               24.6 34.2                                    H      20       400      10  204.0                                                                               18.5                                         H      40       400      10  170.0                                                                               21.5 (28.8-39.7)                             H      80       400       9  131.7                                                                               22.6                                         Controls                                                                              --       --       10  267.0                                                                               22.9 2.8                                     F      2        --       10  188.5                                                                               11.1                                         F      4        --       10  157.5                                                                               13.2 (2.3-3.2)                               F      8        --       10  118.0                                                                               24.6                                         Controls                                                                              --       400      10  272.0                                                                               24.6 3.0                                     F      2        400       9  192.2                                                                               28.2                                         F      4        400      10  168.5                                                                               20.0 (2.2-3.7)                               F      8        400       9  133.3                                                                               19.7                                         Controls                                                                              --       --       10  271.0                                                                               18.2 5.0                                     E      1.5      --       10  209.5                                                                               19.4                                         E      3        --       10  188.5                                                                               12.9 (4.1-6.1)                               E      6        --       10  170.0                                                                               16.5                                         E      12       --       10  154.0                                                                               13.3                                         Controls                                                                              --       400      10  271.0                                                                               18.3 4.3                                     E      1.5      400      10  209.5                                                                               15.9                                         E      3.0      400      10  181.5                                                                               12.0 (3.4-5.0)                               E      6.0      400      10  162.5                                                                               17.2                                         E      12.0     400      10  148.5                                                                               21.9                                         ______________________________________                                          *n = No. of animals                                                      

RESULTS

By virtue of the addition of pirenzepine dihydrochloride (substance A), the ED₅₀ for ulcerogenicity of the tested antiphlogistics in the stomach of the rat undergoes a dose-dependent increase (see table I). The simultaneous oral administration of pirenzepine dihydrochloride, on the other hand, does not lead to a reduction of the acute anti-exudative effect of non-steroidal antiphlogistics on the kaolin- and carrageenin-induced edema of the rat (see tables II and III).

By means of substance A the ulcerogenic effect of non-steroidal antiphlogistics in the stomach of the rat can be weakened in dose-dependent manner. Since the acute antiexudative effect of these non-steroidal antiphlogistics is not reduced by the simultaneous administration of substance A, this anti-ulcerogenic effect of A cannot be caused by a direct interaction with the tested non-steroidal antiphlogistics or by a reduction of their absorption.

The results prove that 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or its non-toxic, pharmaceutically acceptable acid addition salts formed with inorganic or organic acids are able to abolish the gastro-intestinal side-effects (formation of lesions, hemorrhagias and formation of ulcers) of non-steroidal antiphlogistics, while the antiphlogistic activity of these antiphlogistics is fully retained.

The antiphlogistic pharmaceutical compositions according to this invention are characterized in that they contain as an active ingredient any desired non-steroidal antiphlogistic compound or a non-toxic, pharmaceutically acceptable salt thereof in combination with 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a non-toxic, pharmaceutically acceptable salt thereof formed with inorganic or organic acids, where the dosage ratio of the pyridobenzodiazepinone to the antiphlogistic is in the range of 1:500 to 1:2, depending upon the effective strength of the antiphlogistic.

In general, the daily dose rate of 5,11-dihydro-11[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or of a non-toxic acid addition salt thereof is between 0.16 and 0.83 mgm/kg. The novel compositions may also contain other pharmacologically effective compounds and/or inert carriers and/or excipients conventionally used in pharmaceutical compositions.

The following known compounds can be used as antiphlogistic components for the compositions of the present invention:

O-acetyl-salicylic acid,

Flufenisal=2-(acetyloxy)-5-(4-fluoro-phenyl)-benzoic acid,

Diflunisal=2-(hydroxy)-5-(2,4-difluoro-phenyl)-benzoic acid,

Ibuprofen=2-(4-isobutyl-phenyl)-propionic acid,

Indomethacin=1-(4-chloro-benzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid,

Ketoprofen=2-(3-benzoyl-phenyl)-propionic acid,

Suprofen=α-methyl-4-[(2-thienyl)carbonyl]-benzene-acetic acid,

Tolmetin=1-methyl-5-(p-toluoyl)-pyrrol-2-acetic acid and its salts, mainly the 1-methyl-5-(p-toluoyl)pyrrol-2-acetic acid sodium salt dihydrate,

Sulindac=Z-5-fluoro-2-methyl-1(4-methylsulfinyl-benzylidene)indene-3-acetic acid,

Flurbiprofen=2-(2-fluoro-4-biphenylyl)-propionic acid,

Naproxen=(+)-6-methoxy-α-methyl-2-naphthalene-acetic acid,

Fenoprofen=2-(3-phenoxy-phenyl)-propionic acid and its salts, mainly the 2-(3-phenoxy-phenyl)-propionic acid calcium salt dihydrate,

6-Chloro-α-methyl-carbazole-2-acetic acid,

Fenbufen=4-(4-biphenylyl)-4-oxo-butyric acid,

Bucloxinic acid=4-(3-chloro-4-cyclohexyl-phenyl)-4-oxo-butyric-acid,

6,11-Dihydro-11-oxo-dibenz[b,e]oxepine-2-acetic acid,

d-2-(6,11-Dihydro-11-oxo-dibenzo[b,e]thiepin-3-yl)-propionic acid and its non-toxic pharmaceutically acceptable salts formed with inorganic and organic bases,

d-2-(6,11-Dihydro-11-oxo-dibenzo[b,e]oxepin-3-yl)-propionic acid and its non-toxic, pharmaceutically acceptable salts formed with inorganic and organic bases,

d-α-methyl-5-oxo-5H-dibenzo[a,d]cycloheptene-2-acetic acid and its non-toxic, pharmaceutically acceptable salts formed with inorganic and organic bases,

Etodolic acid=1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]-indole-2-acetic acid,

E-4-(2-fluoro-4-biphenylyl)-4-hydroxy-2-butenic acid,

4-(4-biphenylyl)-1-butanol,

Diclofenac=o-[(2,6-dichloro-phenyl)amino]-phenyl-acetic acid and its non-toxic, pharmaceutically acceptable salts formed with inorganic and organic bases, mainly sodium [o-[(2,6-dichlorophenyl)amino]-phenyl]acetate,

Flufenamic acid=2-[[3-(Trifluoromethyl)phenyl]amino]-benzoic acid,

Meclofenamic acid=2-[(2,6-dichloro-3-methyl-phenyl) amino]-benzoic acid and its non-toxic, pharmaceutically acceptable salts formed with inorganic and organic bases, mainly the sodium salt,

Mefenamic acid=2-[(2,3-dimethyl-phenyl)amino]-benzoic acid,

Niflumic acid=2{[3-(trifluoromethyl)phenyl]amino}-3-pyridine-carboxylic acid,

Phenylbutazone=4-(1-butyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine and its non-toxic, pharmaceutically acceptable salts formed with inorganic and organic bases, mainly the sodium salt,

Pyrazinobutazone=equimolecular salt of phenylbutazone and piperazine,

Oxyphenbutazone=4-(1-butyl)-1-(4-hydroxy-phenyl)-2-phenyl-3,5-dioxo-pyrazolidine,

1,4-diphenyl-3,5-dioxo-pyrazolidine and its non-toxic, pharmaceutically acceptable salts formed with inorganic and organic bases,

Feprazone=4-(3-methyl-2-buten-1-yl)-1,2-diphenyl-3,5-pyrazolidinedione,

Azapropazone=5-dimethylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione,

Bumadizone calcium semihydrate=butylmalonic acid mono-(1,2-diphenyl)-hydrazide calcium salt semihydrate,

Sudoxicam=4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide,

Piroxicam=4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide,

Isoxicam=4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide,

4-Hydroxy-2-methyl-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide,

Proquazone=7-methyl-4-phenyl-1-(2-propyl)-2(1H)-quinazolinone,

Flumizol=4,5-bis-(4-methoxy-phenyl)-2-(trifluoromethyl)-imidazole, and

E-{[(p-chloro-α-methyl-benzylidene)amino]oxy}-acetic acid 2-(dimethylamino)ethyl ester hydrochloride.

The present invention also relates to the process for the preparation of the pharmaceutical compositions according to this invention, which comprises combining any non-steroidal antiphlogistic compound or a non-toxic, pharmaceutically acceptable salt thereof with 5,11-dihydro-11[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a non-toxic, pharmaceutically acceptable acid addition salt thereof in the proportion pyridobenzodiazepinone to antiphlogistic from 1:500 to 1:2, and formulating the combination, optionally with other known active ingredients, with customary carriers and/or excipients into tablets, coated pills, powders, syrups, capsules, effervescent tablets, suppositories or the like.

The pharmaceutical compositions according to this invention are administered orally, rectally and/or parenterally, once daily or in several smaller doeses. The preparation of the tablets, coated pills, suppositories, powder mixtures and syrups is performed in known manner; for instance, the tablets are produced by directly compressing a mixture of the active ingredients and the excipients, and the tablets can subsequently optionally be coated with a film which is soluble in the stomach and gastro-intestinal tract. For the preparation of capsules, the mixture of active ingredients and excipients is filled into capsules made of hard gelatin, for example. The carrier substances in the suppositories are vegetable fats for instance hardened vegetable oil or triglycerides of fatty acids with 12 to 18 carbon atoms, and the active ingredients combination is homogeneously distributed therein.

The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 Effervescent tablets with pirenzepine-dihydrochloride and ascorbic acid

The tablet composition is compounded from the following ingredients:

    ______________________________________                                         Pirenzepine dihydrochloride                                                                        10.0 parts                                                 Ascorbic acid       200.0 parts                                                Citric acid, anhydrous                                                                             1060.0 parts                                               Sodium bicarbonate  1670.0 parts                                               Sodium benzoate 40.0 parts                                                     Polyvinylpyrrolidone                                                                               20.0 parts                                                 Total               3000.0 parts                                               ______________________________________                                    

PREPARATION

The pirenzepine dihydrochloride, the ascorbic acid, the citric acid and the sodium bicarbonate are mixed together, and the mixture is moistened with a 10% solution of polyvinylpyrrolidone in ethanol. The moist mass is then granulated and dried at a temperature of 45° C. The dry granulate is admixed with the sodium benzoate, and the composition is compressed into 3000 mgm-tablets. The tablets must be prepared in an air-conditioned room in which the relative humidity is kept below 30%. Each tablet contains 10 mgm of pirenzepine dihydrochloride and 200 mgm of ascorbic acid.

EXAMPLE 2 Tablets with microencapsuled acetylsalicylic acid and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                         Acetylsalicylic acid, microencapsuled                                                                500.0 parts                                              Pirenzepine dihydrochloride                                                                          10.0 parts                                               Lactose               50.0 parts                                               Corn Starch           48.0 parts                                               Stearic acid          4.0 parts                                                Polyvinylpyrrolidone  8.0 parts                                                Total                 620.0 parts                                              ______________________________________                                    

PREPARATION

The acetylsalicylic acid, the pirenzepine dihydrochloride, the lactose and the corn starch are mixed together, and the mixture is moistened with an aqueous 10% solution of polyvinylpyrrolidone in which the stearic acid is dissolved by heating. The moist mass is then granulated and dried at a temperature of 45° C. The dry granulate is compressed into 620 mgm-tablets. Each tablet contains 500 mgm aspirin and 10 mgm pirenzepine dihydrochloride.

EXAMPLE 3 Stomach juice-resistant coated tablets with sodium o-[(2,6-dichloro-phenyl)amino]-phenylacetate and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                         Sodium o-[(2,6-dichloro-phenyl)amino]-                                                                 75.0 parts                                             phenyl-acetate                                                                 Pirenzepine dihydrochloride                                                                           5.0 parts                                               Calcium phosphate      120.0 parts                                             Corn Starch            50.0 parts                                              Soluble starch         8.0 parts                                               Magnesium stearate     2.0 parts                                               Total                  260.0 parts                                             ______________________________________                                    

PREPARATION

The sodium o-[2,6-dichloro-phenyl)amino]-phenyl-acetate, the pirenzepine dihydrochloride, the calcium phosphate and the corn starch are intimately admixed, and moistened with an aqueous 20% solution of the soluble starch. The moist mixture is then granulated through a screen and dried at a temperature of 45° C. The dry granulate is admixed with the magnesium stearate and compressed into 260 mgm-tablets. Subsequently, the tablets are coated with a mixture consisting of anionic polymerizates of methacrylic acid and methacrylates dissolved in an acetone/isopropanol mixture. The coated tablets are then provided in known manner with a thin outer shell consisting of sugar and talcum. The finished coated tablets are polished with beeswax. Each coated tablet contains 75 mgm of sodium o-[2,6-dichloro-phenyl)-amino]-phenylacetate and 5 mgm of pirenzepine dihydrochloride.

EXAMPLE 4 Coated tablets with phenylbutazone and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                          Pirenzepine dihydrochloride                                                                       10.0 parts                                                 Phenylbutazone      200.0 parts                                                Lactose             93.5 parts                                                 Corn Starch         50.0 parts                                                 Cellulose, microcrystalline                                                                        40.0 parts                                                 Polyvinylpyrrolidone                                                                               5.0 parts                                                  Magnesium stearate  1.5 parts                                                  Total               400.0 parts                                                ______________________________________                                    

PREPARATION

The active ingredients are admixed with the lactose, the corn starch and the cellulose, and the mixture is moistened with a 10% solution of the polyvinylpyrrolidone in water. The mass is then granulated and dried at a temperature of 45° C., and the dry granulate is admixed with the magnesium stearate. The mixture is then compressed into 400 mgm-tablets which are subsequently coated with a thin shell consisting essentially of sugar and talcum. The coated tablets are polished with beeswax. Each coated tablet contained 100 mgm of phenylbutazone and 10 mgm of pirenzepine dihydrochloride.

EXAMPLE 5 Suppositories with 4-(1-butyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine and pirenzepine dihydrochloride

The suppositories are compounded from the following ingredients:

    ______________________________________                                         4-(1-butyl)-1,2-diphenyl-3,5-dioxo                                             pyrazolidine            250 parts                                              Pirenzepine dihydrochloride                                                                            25 parts                                               Suppository base                                                               (e.g. cocoa butter)     1425 parts                                             Total                   1700 parts                                             ______________________________________                                    

PREPARATION

After melting the suppository base, the active ingredients are homogeneously suspended therein at 40° C. by intensive stirring. 1700 mgm-portions of the composition are poured into slightly pre-cooled suppository moulds and allowed to harden therein. Each suppository contains 250 mgm of the pyrazolidine compound and 25 mgm of pirenzepine dihydrochloride.

EXAMPLE 6 Ampules

The dry substance ampule contains:

    ______________________________________                                         Pirenzepine dihydrochloride                                                                              10 mgm                                               Mannitol                  50 mgm                                               The solution ampule contains:                                                  4-(1-butyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine                                                          450 mgm                                              Aminophenazone            450 mgm                                              Lidocaine                 35 mgm                                               Sodium hydroxide          55 mgm                                               Distilled water           ad 3.0 ml                                            ______________________________________                                    

PREPARATION

The pirenzepine dihydrochloride is, together with the mannitol, dissolved in ampule water; 1 ml-portions of the solution are filled into 5 ml-injection bottles and lyophilized according to known methods.

For parenteral administration, the contents of an ampule with the dry substances and the contents of a solution ampule, which comprises the antiphlogistics and the local anaesthetic, are combined and immediately injected thereafter.

EXAMPLE 7 Soluble Granulate

Composition of the granulate:

    ______________________________________                                         Acetylsalicylic acid                                                                             5.0 parts                                                    Pirenzepine dihydrochloride                                                                      0.1 parts                                                    Sodium benzoate   0.2 parts                                                    Citric acid       0.1 parts                                                    Yellow-orange 11963                                                                              0.006 parts                                                  Sugar             19.094 parts                                                 Karion instant    15.0 parts                                                   Satiagum          0.25 parts                                                   Banana 54330      0.2 parts                                                    Caramel 52929     0.05 parts                                                   Total             40.000 parts                                                 ______________________________________                                    

The ingredients are well pulverized and admixed, and the mixture is filled in suitable bottles.

40 gm of the soluble granulate are dissolved in 100 ml of water before use. The solution contains 5 gm of aspirin and 0.1 gm of pirenzepine dihydrochloride.

EXAMPLE 8 Gelatin capsule with inserted core

    ______________________________________                                         Capsule ingredients:                                                                               mgm capsule                                                ______________________________________                                         Acetylsalicylic acid, crystalline                                                                  330.0                                                      Pirenzepine dihydrochloride                                                                        10.0                                                       Corn starch, dried  78.0                                                       Lactose, pulverized 10.0                                                       Aluminum stearate   2.0                                                                            430.0                                                      ______________________________________                                    

    ______________________________________                                         Ingredients of the core:                                                       ______________________________________                                         2,6-bis (diethanolamino)-4,8-dipiperidino-                                     pyrimido [5,4-d]pyrimidine                                                                             75.0 mgm                                               Polyvinylpyrrolidone K 30                                                                              2.5 mgm                                                Formaldehyde gelatin    6.5 mgm                                                Magnesium stearate      1.0 mgm                                                ______________________________________                                    

    ______________________________________                                         Coating:                                                                       ______________________________________                                         Talcum         about 13.4 mgm                                                  Sugar          about 4.2 mgm                                                   Gum arabic     about 2.4 mgm                                                   Core + coating 105.0 mgm                                                       ______________________________________                                    

The ingredients of the capsule are ground, mixed and filled into gelatine capsules; subsequently, by means of an appropriate machine, the core consisting of the above mentioned ingredients is put into the capsule, and the capsule was closed. The core is compressed and coated in the usual way. Each capsule contains 75 mgm of 2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine, 330 mgm of acetylsalicyclic acid and 10 mgm of pirenzepine dihydrochloride.

EXAMPLE 9 Effervescent tablets with pirenzepine-dihydrochloride and 2-(4-isobutyl-phenyl)-propionic acid

The tablet composition is compounded from the following ingredients:

    ______________________________________                                         Pirenzepine dihydrochloride                                                                         10.0 parts                                                2-(4-Isobutyl-phenyl)-propionic acid                                                                200.0 parts                                               Citric acid, anhydrous                                                                              1060.0 parts                                              Sodium bicarbonate   1670.0 parts                                              Sodium benzoate      40.0 parts                                                Polyvinylpyrrolidone 20.0 parts                                                Total                3000.0 parts                                              ______________________________________                                    

PREPARATION

The pirenzepine dihydrochloride, the 2-(4-isobutyl-phenyl)-propionic acid, the citric acid and the sodium bicarbonate are mixed together, and the mixture is moistened with a 10% solution of polyvinylpyrrolidone in ethanol. The moist mass is then granulated and dried at a temperature of 45° C. The dry granulate is admixed with the sodium benzoate, and the composition is compressed into 3000 mgm-tablets. The tablets must be prepared in an air-conditioned room in which the relative humidity is kept below 30%. Each tablet contains 10 mgm of pirenzepine dihydrochloride and 200 mgm of 2-(4-isobutyl-phenyl)-propionic acid.

EXAMPLE 10 Tablets with microencapsuled 2-(4-isobutyl-phenyl)-propionic acid and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                         2-(4-Isobutyl-phenyl)-propionic acid,                                          microencapsuled       500.0 parts                                              Pirenzepine dihydrochloride                                                                          10.0 parts                                               Lactose               50.0 parts                                               Corn starch           48.0 parts                                               Stearic acid          4.0 parts                                                Polyvinylpyrrolidone  8.0 parts                                                Total                 620.0 parts                                              ______________________________________                                    

PREPARATION

The 2-(4-isobutyl-phenyl)-propionic acid, the pirenzepine dihydrochloride, the lactose and the corn starch are mixed together, and the mixture is moistened with an aqueous 10% solution of polyvinylpyrrolidone in which the stearic acid is dissolved by heating. The moist mass is then granulated and dried at a temperature of 45° C. The dry granulate is compressed into 620 mgm-tablets. Each tablet contains 500 mgm 2-(4-isobutyl-phenyl)-propionic acid and 10 mgm pirenzepine dihydrochloride.

EXAMPLE 11 Stomach juice-resistant coated tablets with 2-(4-isobutyl-phenyl)-propionic acid and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                         2-(4-Isobutyl-phenyl)-propionic acid                                                                75.0 parts                                                Pirenzepine dihydrochloride                                                                         5.0 parts                                                 Calcium phosphate    120.0 parts                                               Corn Starch          50.0 parts                                                Soluble starch       8.0 parts                                                 Magnesium stearate   2.0 parts                                                 Total                260.0 parts                                               ______________________________________                                    

PREPARATION

The 2-(4-isobutyl-phenyl)-propionic acid, the pirenzepine dihydrochloride, the calcium phosphate and the corn starch are intimately admixed, and moistened with an aqueous 20% solution of the soluble starch. The moist mixture is then granulated through a screen and dried at a temperature of 45° C. The dry granulate is admixed with the magnesium stearate and compressed into 260 mgm-tablets. Subsequently, the tablets are coated with a mixture consisting of anionic polymerizates of methacrylic acid and methacrylates dissolved in an acetone/isopropanol mixture. The coated tablets are then provided in known manner with a thin outer shell consisting of sugar and talcum. The finished coated tablets are polished with beeswax. Each coated tablet contains 75 mgm of 2-(4-isobutyl-phenyl)-propionic acid and 5 mgm of pirenzepine dihydrochloride.

EXAMPLE 12 Coated tablets with 2-(4-isobutyl-phenyl)-propionic acid and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                         Pirenzepine dihydrochloride                                                                         10.0 parts                                                2-(4-Isobutyl-phenyl)-propionic acid                                                                200.0 parts                                               Lactose              93.5 parts                                                Corn starch          50.0 parts                                                Cellulose, microcrystalline                                                                         40.0 parts                                                Polyvinylpyrrolidone 5.0 parts                                                 Magnesium stearate   1.5 parts                                                 Total                400.0 parts                                               ______________________________________                                    

PREPARATION

The active ingredients are admixed with the lactose, the corn starch and the cellulose, and the mixture is moistened with a 10% solution of the polyvinylpyrrolidone in water. The mass is then granulated and dried at a temperature of 45° C., and the dry granulate is admixed with the magnesium stearate. The mixture is then compressed into 400 mgm-tablets which are subsequently coated with a thin shell consisting essentially of sugar and talcum. The coated tablets are polished with beeswax. Each coated tablet contains 100 mgm of 2-(4-isobutyl-phenyl)-propionic acid and 10 mgm of pirenzepine dihydrochloride.

EXAMPLE 13 Coated tablets with 2-(4-isobutyl-phenyl)-propionic acid and pirenzepine dihydrochloride

The tablets are compounded from the following ingredients:

    ______________________________________                                         Pirenzepine dihydrochloride                                                                         5.0 parts                                                 2-(4-Isobutyl-phenyl)-propionic acid                                                                50.0 parts                                                Lactose              75.0 parts                                                Corn starch          34.0 parts                                                Gelatin              10.0 parts                                                Carboxy methyl cellulose                                                                            5.0 parts                                                 Magnesium stearate   1.0 parts                                                 Total                180.0 parts                                               ______________________________________                                    

PREPARATION

An intimate mixture of the active ingredients, the corn starch and the lactose is moistened with an aqueous 75% solution of the gelatin, the moist mass is granulated through a 1.5 mm-mesh screen and dried at a temperature of 45° C.

The dry granulate is then admixed with the carboxy methyl cellulose and the magnesium stearate, and the composition is compressed into 180 mgm-tablets which are then coated with a thin shell consisting essentially of sugar and talcum. The coated tablets are polished with beeswax. Each coated tablet contains 50 mgm of 2-(4-isobutyl-phenyl)-propionic acid and 5 mgm of pirenzepine dihydrochloride.

EXAMPLE 14 Suppositories with 2-(4-isobutyl-phenyl)-propionic acid and pirenzepine dihydrochloride

The suppositories are compounded from the following ingredients:

    ______________________________________                                         2-(4-Isobutyl-phenyl)-propionic acid                                                                    100 parts                                             Pirenzepine dihydrochloride                                                                             25 parts                                              Suppository base (e.g. cocoa butter)                                                                    1575 parts                                            Total                    1700 parts                                            ______________________________________                                    

PREPARATION

After melting the suppository base, the active ingredients are homogeneously suspended therein at 40° C. by intensive stirring. 1700 mgm-portions of the composition are poured into slightly pre-cooled suppository moulds and allowed to harden therein. Each suppository contains 100 mgm of 2-(4-isobutyl-phenyl)-propionic acid and 25 mgm of pirenzepine dihydrochloride.

EXAMPLE 15 Gelatin capsule with inserted core

    ______________________________________                                         Capsule ingredients:  mgm/capsule                                              ______________________________________                                         2-(4-Isobutyl-phenyl)-propionic acid                                                                 330.0                                                    Pirenzepine dihydrochloride                                                                          10.0                                                     Corn starch, dried    78.0                                                     Lactose, pulverized   10.0                                                     Aluminum stearate     2.0                                                                            430.0                                                    ______________________________________                                    

    ______________________________________                                         Ingredients of the core:                                                       ______________________________________                                         2,6-bis (diethanolamino)-4,8-dipiperidino-                                     pyrimido [5,4-d]pyrimidine                                                                             75.0 mgm                                               Polyvinylpyrrolidone K 30                                                                              2.5 mgm                                                Formaldehyde gelatin    6.5 mgm                                                Magnesium stearate      1.0 mgm                                                ______________________________________                                    

    ______________________________________                                         Coating:                                                                       ______________________________________                                         Talcum         about 13.4 mgm                                                  Sugar          about 4.2 mgm                                                   Gum arabic     about 2.4 mgm                                                   Core + coating 105.0 mgm                                                       ______________________________________                                    

The ingredients of the capsule are ground, mixed and filled into gelatine capsules; subsequently, by means of an appropriate machine, the core consisting of the above mentioned ingredients is put into the capsule, and the capsule was closed. The core is compressed and coated in the usual way. Each capsule contains 75 mgm of 2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine, 330 mgm of 2-(4-isobutyl-phenyl)-propionic acid and 10 mgm of pirenzepine dihydrochloride.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims. 

We claim:
 1. The method of suppressing the undesirable gastro-intestinal side-effects produced by administering 4-(4-biphenylyl)-butanol to a warm-blooded animal in need thereof, which comprises simultaneously administering to said animal 1 part by weight of 5,11-dihydro-11-[(4-methyl-1-piperazinyl)-acetyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one per 2 to 500 parts by weight of 4-(4-biphenylyl)-butanol.
 2. An antiphlogistic pharmaceutical composition consisting essentially of an inert pharmaceutical carrier, an effective antiphlogistic amount of 4-(4-biphenylyl)-butanol, and 5,11-dihydro-11-[(4-methyl-1-piperazinyl)-acetyl]-6H-pyrido[2,3b][1,4]benzodiazepin-6-one or a non-toxic, pharmaceutically acceptable acid addition salt thereof, where the weight ratio of 5,11-dihydro-11-[(4-methyl-1-piperazinyl)-acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one or a non-toxic, pharmaceutically acceptable acid addition salt thereof to 4-(4-biphenylyl)-butanol is within the range of 1:500 parts to 1:2 parts. 